Indigenous population, travelers and troops present in Africa and South America are clearly at risk of exposure to several arenaviruses. Several human pathogenic arenaviruses, e.g., Lassa and Junin viruses, are listed on the NIAID's Priority Pathogens and CDC's Bioterrorism Agents Lists and can cause a deadly hemorrhagic fever. No effective and safe vaccine is currently available to combat these diseases. In addition, effective arenavirus vaccines are needed for the Strategic National Stockpile in preparation for a potential bioterror attack in the United States. A commonly used, safe vaccine platform based on the Yellow fever (YF) vaccine 17D will be exploited to generate a protective vaccine against arenaviral infections. The live-attenuated YF-17D virus vaccine strain has been used for human immunization since 1936. More than 500 million people have been vaccinated with YF-17D over the past 70 years, and the vaccine has a truly remarkable record of safety and efficacy. A single subcutaneous immunization with YF-17D elicits long-lasting protective antibodies and cellular immune responses. We will use this vaccine platform to generate multivalent arenavirus vaccines protecting against YFV and different arenaviruses. This new vaccine approach represents an important upgrade/replacement for the standard YF-17D vaccine that will provide immunity to both YF and important arenaviruses. Besides the overall known safety of the vaccine platform, the published proof of concept for the use of this platform to protect against a deadly arenavirus, and the advantage of targeting different viral diseases in a similar geographical location (e.g., YF and Lassa fever - Lassa virus in West Africa;YF and Argentine hemorrhagic fever- Junmn virus in South America) makes this approach ideal as a prophylactic treatment for protecting indogenous populations, travelers and warfighters. Importantly, the multivalent YF-17D vaccine platform is readily adaptable for the generation of immunity to other viral families, such as bunyaviruses (Rift Valley fever virus, Crimean-Congo hemorrhagic fever virus) and henipaviruses (Nipah virus, Hendra virus), all of which present (i) a real threat to the indigenous populations and travelers in locations including Africa, Middle East and Southeast Asia, and (ii) a bioterror threat to the United States and its allies. PUBLIC HEALTH RELEVANCE: Yellow fever viruses and arenaviruses (e.g., Junin, Lassa) that cause hemorrhagic fever (HF) are serious health concerns - as emerging diseases as well as bioterror threats. We will use the safe and approved Yellow Fever 17D vaccine as a platform to develop a multivalent Yellow fever-arenavirus vaccine. This new multivalent vaccine will simultaneously protect against several hemorrhagic fever-causing pathogens.